Connecting two pathways through Ca 2+ signaling: NLRP3 inflammasome activation induced by a hypermorphic PLCG2 mutation.

ABSTRACT: OBJECTIVE:We previously reported that p.Ser707Tyr, a novel variant in phospholipase C?2 (PLC?2), is the cause of a dominantly inherited autoinflammatory disease, autoinflammation and PLC?2-associated antibody deficiency and immune dysregulation (APLAID). The hypermorphic mutation enhances PLC?2 activity and causes an increase in intracellular Ca2+ release from endoplasmic reticulum stores. Because increased intracellular Ca2+ signaling has been associated with NLRP3 inflammasome activation, we studied the role of the NLRP3 inflammasome in the pathogenesis of APLAID. METHODS:Human peripheral blood mononuclear cells (PBMCs) were isolated from healthy control subjects and 2 patients with APLAID. Inflammasome activation was analyzed by Western blotting. Intracellular Ca2+ levels were measured with a FLIPR Calcium 4 assay kit. RESULTS:Cells from the patients had elevated basal levels of intracellular Ca2+, and the intracellular Ca2+ flux triggered by extracellular CaCl2 was substantially enhanced. Patient PBMCs secreted interleukin-1? in response to lipopolysaccharide priming alone, and this effect was attenuated by treatment with a PLC inhibitor, intracellular Ca2+ blockers, or an adenylate cyclase activator. CONCLUSION:Our findings suggest that the inflammation in patients with APLAID is partially driven by activation of the NLRP3 inflammasome. These data link 2 seemingly distinct molecular pathways and provide new insights into the pathogenesis of APLAID and autoinflammation.

SUBMITTER: Chae JJ 

PROVIDER: S-EPMC4369162 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature